Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

作者：Cindy Wen, Michael Margolis, Rujia Dai, Pan Zhang, Pawel F. Przytycki, Daniel Vo, Arjun Bhattacharya, Nana Matoba, Miao Tang, Chuan Jiao, Minsoo Kim, Ellen Tsai, Celine Hoh, Nil Aygün, Rebecca L. Walker, Christos Chatzinakos, Declan Clarke, Henry Pratt, Mette A. Peters, Mark Gerstein, Nikolaos P. Daskalakis, Zhiping Weng, Andrew E. Jaffe, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger, Nicholas J. Bray, Nenad Šestan, Daniel H. Geschwind, Kathryn Roeder, Alexander Gusev, Bogdan Paşaniuc, Jason L. Stein, Michael I. Love, Katherine S. Pollard, Chunyu Liu, Michael J. Gandal, Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, José Juan Almagro Armenteros, Brian J. Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul Bharadwaj, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A. Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H. Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-fan Chien, Zhiyuan Chu, Ashley Clement, Leonardo Collado‐Torres, Gregory M. Cooper, Gregory E. Crawford, José Dávila-Velderrain, Amy Deep‐Soboslay, Chengyu Deng, Christopher P. DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc M. Duong, Cagatay Dursun, Nicholas J. Eagles, Jonathan I. Edelstein, Prashant S. Emani, John F. Fullard, Kiki Galani, Timur R. Galeev, Sophia C. Gaynor, Kiran Girdhar, Fernando S. Goes, William J. Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C. Hicks, Marcus Ho, Li‐Lun Ho, Gabriel E. Hoffman, Yi‐Ling Huang, Louise A. Huuki-Myers, Ahyeon Hwang, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew L. Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Steven P. Kleopoulos, Alexey Kozlenkov, Arnold R. Kriegstein, Anshul Kundaje, Soumya Kundu, Che-Yu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Shuang Liu, Shaoke Lou, Jacob M. Loupe, Dan Lu, Shaojie Ma, Liang Ma, Jessica Mariani, Keri Martinowich, Kristen R. Maynard, Samantha Mazariegos, Ran Meng, R Myers, Courtney Micallef, Tatiana Mikhailova, Guo‐li Ming, Shahin Mohammadi, Emma Monte, Kelsey S. Montgomery, Jill E. Moore, Jennifer Moran, Eran A. Mukamel, Angus C. Nairn, Charles B. Nemeroff, Pengyu Ni, Scott Norton, Tomasz J. Nowakowski, Larsson Omberg, Stephanie C. Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Alex A. Pollen, Carolin Purmann, Zhaohui Qin, Pingping Qu, Diana Quintero, Towfique Raj, Ananya S. Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J. Ressler, Deanna Ross, Panos Roussos, Joel Rozowsky, M Hall Ruth, W. Brad Ruzicka, Stephan Sanders, Juliane M. Schneider, Soraya Scuderi, Robert Sebra, Nicholas T. Seyfried, Zhiping Shao, Nicole Shedd, Annie W. Shieh, Joo Heon Shin, Mario Škarica, Clara Snijders, Hongjun Song, Matthew W. State, Marilyn Steyert, Sivan Subburaju, Thomas C. Südhof, M Snyder, Ran Tao, Karen Therrien, Li‐Huei Tsai, Alexander E. Urban, Flora M. Vaccarino, Harm van Bakel, Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H. Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Wei Yu, Annika K. Weimer, Sean Whalen, Kevin P. White, A. Jeremy Willsey, Hyejung Won, Wing Kee Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X. Yap, Biao Zeng, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane Zeier, Trisha M. Zintel · 发表于：Science · 年份：2024 · DOI：10.1126/science.adh0829 · 被引用次数：51 · 研究领域：Genetic Associations and Epidemiology、Genomic variations and chromosomal abnormalities、Genomics and Chromatin Dynamics

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.